Loss of memory is an important medical and social issue in our aging society. Working memory is one form of memory that shows declines with increasing age and it is known that humans and animals rely on the executive functions of the prefrontal cortex for proper performance of working memory tasks. A better understanding of the cellular and molecular dysfunctions that occur in the prefrontal cortex during aging and that impact on prefrontal functions, such as working memory, should lead to better interventions into age-related memory declines. The N- methyl-D-aspartate (NMDA) receptor, known to be important in learning and memory processes, shows decreases in transmitter binding in frontal cortical regions (including prefrontal regions) of C57B1/6 mice that are correlated with spatial memory declines. Native NMDA receptors are assembled from multiple types of subunits and differences in subunit composition of the receptor can influence the electrophysiological and pharmacological properties of the receptor. The mRNA expression of the epsilon2 (epsilon2) subunit appears to decrease significantly in the frontal regions of the aging mouse brain, similar to the binding changes. This proposal is designed to investigate the functional consequences of changes in NMDA receptor subunit composition in the aging animal and to address the hypothesis that functional changes during aging in the NMDA receptor, caused by changes in subunit composition, induce declines in prefrontal cognitive abilities. The project will 1) characterize the spatial working memory performance of 3 different age groups (3, 10, and 26 months) of mice using the radial arm maze; 2) confirm the expression of NMDA receptor subunit composition in the prefrontal cortex from the same mice using RT-PCR techniques; 3) determine the effect of aging on biophysical properties of the NMDA receptor from these mice using two-electrode voltage clamp (TEVC) techniques on a Xenopus oocyte expression system; and 4) determine the effect of aging on pharmacological properties of the NMDA receptor, again by performing TEVC on Xenopus oocytes. Results from Aim number 1 will be compared with those from Aims number 2-4. The results of these studies should provide a mechanistic insight into our understanding of memory loss during aging. The proposed techniques in Specific Aims number 2-4 represent new methodologies for the PI and the acquisition of these techniques is essential to the evaluation of the role that age- associated changes in NMDA receptors play in memory loss in the elderly.